Adult hematopoietic stem cells (HSC) are quiescent most of the time, and how HSC switch from quiescence to proliferation following hematopoietic stress is unclear. Here we demonstrate that upon stress the coxsackievirus and adenovirus receptor CAR (also known as CXADR) is upregulated in HSC and critical for HSC entry into the cell cycle. Wild-type HSC were detected with more rapid repopulation ability than the CAR knockout counterparts. After fluorouracil treatment, CAR knockout HSC had lower levels of Notch1 expression and elevated protein level of Numb, a Notch antagonist. The Notch signaling inhibitor DAPT, dominant negative form of MAML (a transcriptional coactivator of Notch), or dominant negative mutant of LNX2 (an E3 ligase that acts on Numb and binds to CAR), all were capable of abrogating the function of CAR in HSC. We conclude that CAR activates Notch1 signaling by downregulating Numb protein expression to facilitate entry of quiescent HSC into the cell cycle during regeneration.
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